Reference: June 2025 | Issue 6 | Vol 11 | Page 30
Rheumatoid arthritis (RA) affects an estimated 40,000 people in Ireland, with disease costs of around €20,000 per patient per year and an overall cost to the health system of approximately €544 million. Only one in four RA patients achieve remission and a significant proportion of patients have sub-optimal responses or no response to currently available therapies.
As it is impossible to predict who will develop severe, erosive disease and who will respond to treatment, a trial-and-error approach prevails. This can lead to potential irreversible joint damage before the patient has received the correct treatment.
However, a recent study published by researchers at Trinity College Dublin and St Vincent’s University Hospital, Dublin, proposes a better understanding of the site of inflammation in RA, which could allow for the development of new treatment strategies or predictive biomarkers, which could support a personalised medicine approach.
This work was led by Prof Ursula Fearon and Dr Megan Hanlon from the Molecular Rheumatology Group in Trinity, and by Prof Douglas Veale (RIP) from St Vincent’s University Hospital.
Study details
The team performed an in-depth investigation of the macrophages that reside in the synovium of RA patients, individuals at risk of RA, and healthy controls. Researchers demonstrated, for the first time, the presence of a dominant macrophage subtype (CD40-expressing CD206+CD163+) in the inflamed RA synovium which, importantly, was associated with disease-activity and treatment response.
The team identified that these cells play a protective role in the joint in health, but in disease – for unknown reasons – become pro-inflammatory and release cytokines that induce inflammation, and also have the ability to activate invasive fibroblasts which leads to cartilage and bone destruction.
Researchers identified that the pro-inflammatory status of these macrophages is maintained by specific signalling and metabolic pathways within the joint, the targeting of which may induce resolution of inflammation. Importantly, the team identified that these changes occurred before disease onset.
Combined, these findings identify the presence of an early pathogenic macrophage cell/gene signature that shapes the RA joint inflammatory environment and represents a unique opportunity for early diagnosis and therapeutic intervention.
Key findings
- Identification of a novel macrophage subtype in the joint and evidence that these are the dominant macrophages in patients with active RA.
- This macrophage subtype is highly pro-inflammatory and releases cytokines that cause further inflammation in the joint.
- These cells activate fibroblast in the joint that specifically invade and break down adjacent cartilage and bone.
- The frequency of this cell type in the joint at baseline predicts response to treatment and subsequent disease flare.
- In parallel, the protective barrier macrophages (CX3CR1+) are depleted in established RA, showing a switch in the dominance of joint macrophages from protective to pro-inflammatory macrophages.
- Crucially, the identification of a dominant macrophage subtype (CD40-expressing CD206+CD163+) suggests targeting of CD40 signalling could represent a new strategy for patients who currently do not respond to treatment.
- Most importantly, the team identified that these cells are present and become activated in individuals at risk of developing RA prior to clinical signs and symptoms. Identification of the early cellular/gene patterns and cues that transform protective macrophage population into a dysfunctional pro-inflammatory macrophage may provide opportunities to target early and reinstate joint homeostasis in RA patients.
Prof Fearon said: “This is an important breakthrough in our understanding of what goes wrong at the initial stages of disease in RA, which also has an impact on patients’ progression and relapse. We have identified a dominant macrophage subtype/gene signature associated with driving the pro-inflammatory responses early in disease and therefore reprogramming of macrophages towards resolution of inflammation has the potential to be therapeutically targeted.”
Dr Hanlon, Post-Doctoral Fellow in Molecular Rheumatology, School of Medicine (at the time of the study, and now based in Harvard University), said: “The presence of these macrophages in individuals at risk of developing RA highlights the possibility of an early cellular biomarker of disease onset, resulting in early treatment intervention.”
Reference
Hanlon MM, Smith CM, Canavan M, Neto NGB, Song Q, Lewis MJ, et al. Loss of synovial tissue macrophage homeostasis precedes rheumatoid arthritis clinical onset. Sci Adv. 2024 Sep 27;10(39):eadj1252
